Assessment and Reporting of Adverse Drug Reactions

Question 1:
Safety data is only collected during the later phases of the clinical development program for a medical product.
True or False?

Question 2:
Health care providers are required to report all adverse drug events.
True or False?

Question 3:
The frequency of experiencing adverse drug event X for a given drug can be determined through spontaneous reporting systems.
True or False?

Question 4:
A safety signal could be:
A. A new, previously unknown, adverse event
B. A new drug interaction
C. An observed change in quantity, severity, or in the affected population of a known adverse event
D. All of the above

The patient is a 59-year-old male with Type 2 diabetes, hyperlipidemia, and hypertension. He has no history of liver disease.

Background:

• Started Drug X on Feb 11, 2016
• Other medications: simvastatin and lisinopril
• Labs drawn on Feb 11 revealed liver enzymes, INR, creatinine, and bilirubin all within normal limits
• No alcohol use
• 8 weeks after starting Drug X, patient presented to ER with 5-day history of jaundice, dark urine, and nausea/vomiting
• He was admitted to ICU and subsequently diagnosed with acute liver failure
• Drug X stopped upon admission
• Viral hepatitis was ruled out
• 7 days after stopping the medication, all lab values returned to normal

1. List two reasons why this patient may be at risk for an adverse event.

2. Is a temporal relationship of acute liver failure with drug X reported in this case?
Yes or No

3. Based on the information on recovery of acute liver failure reported in this case, the patient experienced:
A. Positive rechallenge
B. Negative dechallenge
C. Positive dechallenge
D. Negative rechallenge

4. Name two characteristics in this case that support a causal association of acute liver failure with Drug X.

5. Based on this case, should regulatory action be taken to add acute liver failure to the label? If not, what additional information may be helpful?

Question 1:
List two reasons why this patient may be at risk for an adverse event.

Answer: This patient may be at risk for an adverse event because of his age, because he is taking multiple medications, has comorbid diseases, and his use of a drug is chronic (use for 8 weeks).

Question 2:
Is a temporal relationship of acute liver failure with drug X reported in this case?

Answer: Yes.

Question 3:
Based on the information on recovery of acute liver failure reported in this case, the patient experienced:
A. Positive rechallenge
B. Negative dechallenge
C. Positive dechallenge
D. Negative rechallenge

Answer: Positive dechallenge.

Question 4:
Name two characteristics in this case that support a causal association of acute liver failure with Drug X.

Answer: Characteristics include temporal association, positive dechallenge, alternate causes (viral hepatitis, alcohol use) ruled out, and no prior history of liver disease.

Question 5:
Based on this case, should regulatory action be taken to add acute liver failure to the label? If not, what additional information may be helpful?

Answer: These decisions are not always easy and straightforward. In this case, additional information would be helpful to understand several unknown factors:

• When were lisinopril and simvastatin started and were they discontinued or continued after the event? Simvastatin is labeled for increase LFTs and lisinopril for hepatic failure: two places to check labels (package inserts or prescribing information) are Drugs@FDA or DailyMed (https://dailymed.nlm.nih.gov/).
• Are there any other cases? Usually more than one case is needed.
• Is there evidence for biologic plausibility? Are other drugs in the same class as Drug X known to cause liver injury?
• What is the exposure to this drug? For example, did this one patient experience liver failure out of only 10 patients exposed to Drug X (10%), or did this one patient experience liver failure out of millions of patients exposed to Drug X?

Question 1:
Safety data is only collected during the later phases of the clinical development program for a medical product.
True or False?

Answer: False
Safety data collection is NOT limited to the later phases of the clinical development program, but are collected throughout the lifecycle of FDA-regulated products.

Question 2:
Health care providers are required to report all adverse drug events.
True or False?

Answer: False
Reporting of adverse drug reactions is voluntary for health care providers, but is required for manufacturers. However, it is important for health care providers to report ADRs to support safe medication use.

Question 3:
The frequency of experiencing adverse drug event X for a given drug can be determined through spontaneous reporting systems.
True or False?

Answer: False
FDA does not receive reports for every adverse event because it is a voluntary system.
• Frequency cannot be determined because we do not know the total number
of people experiencing an ADR (numerator) or the total number of people receiving the drug (denominator).
• The FDA Adverse Event Reporting System (FAERS) has limitations, e.g. time on market can influence the number of reports, and reports can increase due to publicity (when an adverse event with a drug is reported in the news).

Question 4:
A safety signal could be:
A. A new, previously unknown, adverse event
B. A new drug interaction
C. An observed change in quantity, severity, or in the affected population of a known adverse event
D. All of the above

Answer: D (All of the above)
Illustrations of safety signals include (1) new unlabeled adverse events, (2) an observed increase in a labeled event (already listed in the package insert) or a greater severity or specificity of a labeled event, (3) an unrecognized drug-drug interaction, or (4) a newly identified at-risk population (e.g. patients with kidney disease).